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ToxSci Advance Access published online on June 2, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi212
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received March 25, 2005
Accepted May 23, 2005

Respiratory Toxicology

Transcriptional and Posttranscriptional Inhibition of Lysyl Oxidase Expression by Cigarette Smoke Condensate in Cultured Rat Fetal Lung Fibroblasts

Song Gao 1, Keyang Chen 1, Yinzhi Zhao 1, Celeste B. Rich 1, Lijun Chen 1, Sandy J. Li 1, Paul Toselli 1, Phillip Stone 1, and Wande Li 1*

1 Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA

* To whom correspondence should be addressed.
Wande Li, E-mail: wandeli{at}bu.edu


  Abstract

Lysyl oxidase (LO) catalyzes crosslinking of collagen and elastin essential for maintaining the structural integrity of the lung extracellular matrix (ECM). To understand mechanisms of cigarette smoke (CS)-induced emphysema, we investigated effects of cigarette smoke condensate (CSC), the particulate matter of CS, on LO mRNA expression in cultured rat fetal lung fibroblasts (RFL6). Exposure of RFL6 cells to 0-120 µg CSC/ml for 24 h induced a dose-dependent inhibition of LO steady-state mRNAs, for example, reducing transcript levels to below 10% of the control in cells incubated with 80-120 µg CSC/ml. Nuclear run-on assays indicated a marked reduction in LO relative transcriptional rates amounting to 27.7% of the control in cells treated with 120 µg CSC/ml. The actinomycin D-chase assay showed that CSC enhanced the instability of LO transcripts. The t1/2 for LO mRNA decay was decreased from 24 h in the control to 4.5 h in cells treated with 120 µg CSC/ml. Moreover, 80-120 µg CSC/ml also inhibited LO promoter activity as revealed by suppression of reporter gene expression in cells transfected with LO promoter-luciferase vectors. Thus, inhibition of LO transcription initiation and enhancement of LO mRNA instability both contributed to downregulation of LO steady-state mRNA in CSC-treated cells. Note that inhibition of LO mRNA expression by CSC was closely accompanied by markedly decreased levels of transcripts of collagen type I and tropoelastin, two substrates of LO. Thus, transcriptional perturbation of LO and its substrates may be a critical mechanism for ECM damage in CS-induced emphysema.

Keywords: cigarette smoke condensate; lysyl oxidase relative transcriptional rate; lysyl oxidase mRNA stability; lysyl oxidase promoter activity; collagen type I; elastin.
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